PROJECT SUMMARY The alkylpiperidine alkaloids are a class of natural products isolated from marine sponges possessing diverse biological activity, including tumor cell cytotoxicity, antimalarial, antitubercular, and antibacterial properties. One such member of this class of natural products is arenosclerin, which has preliminarily been reported as possessing antibacterial activity against several antibiotic-resistant clinical isolates and potent cytotoxicity against several tumor cell lines. While arenosclerin and related family members have preliminarily been associated with clinically-relevant biological activity, further evaluation has been limited given that these natural products can only be isolated in small quantities. Providing an efficient synthetic route to access arenosclerin and related alkaloids would enable further biological study. The tetracyclic structure of arenosclerin consists of a bis-piperdine core appended to two 17-member peripheral macrocycles. This study proposes an efficient total synthesis of arenosclerin, which could also be used to synthesize related members of the alkylpiperidine family. In Aim 1, development of a cycloaddition-fragmentation strategy is described, which would allow access to bis- piperidinyl ring systems present in several biologically active natural products, including arenosclerin. In Aim 2, a total synthesis of arenosclerin is proposed whereby a cycloaddition-fragmentation strategy would afford the target bis-piperidine core, which could then be further elaborated to arenosclerin using a flexible late-stage cross-coupling strategy to close the two remaining macrocycles. In Aim 3, this proposed study details preliminary evaluation of the effect of arenosclerin and its synthetic precursors on the growth inhibition of both sensitive and drug-resistant pathogens. These aims together will provide an efficient route to access arenosclerin, preliminary data toward investigating one facet of arenosclerin's unique biological activity, and allow for future access and evaluation of related alkylpiperidine alkaloids.